Compounds derived from 4-amino-n-(4-aminophenyl) benzamide and analogues and use thereof

Abstract

The present invention relates to compounds of formula (I), in addition to the use thereof for the treatment and/or prevention of diseases caused by protozoa, especially those belonging to the genus Leishmania or Trypanosoma . The present invention likewise relates to pharmaceutical compositions comprising said compounds.

1 . A compound of general formula (I) 
       
         
           
           
               
               
           
         
         or any of the pharmaceutically acceptable isomers, solvates or salts thereof, wherein: 
         R 1  and R 2  are independently selected from H, O i Pr and halogen; 
         R 3  and R 3 ′ are independently selected from 
       
       
         
           
           
               
               
           
         
         Z is selected from 
       
       
         
           
           
               
               
           
         
         X and Y are independently selected from CH and N, 
         for use thereof as a medicament. 
       
     
     
         2 . The compound for use, according to  claim 1 , wherein R 1  and R 2  are the same. 
     
     
         3 . The compound for use, according to  claim 2 , wherein R 1  and R 2  are H. 
     
     
         4 . The compound for use, according to  claim 2 , wherein R 1  and R 2  are Cl. 
     
     
         5 . The compound for use, according to  claim 2 , wherein R 1  and R 2  are O i Pr. 
     
     
         6 . The compound for use, according to  claim 2 , wherein R 1  and R 2  are F. 
     
     
         7 . The compound for use, according to  any of the preceding claims , wherein X and Y are CH. 
     
     
         8 . The compound for use, according to  any of the preceding claims 1 to 6 , wherein X is CH and Y is N. 
     
     
         9 . The compound for use, according to  any of the preceding claims 1 to 6 , wherein X and Y are both N. 
     
     
         10 . The compound for use, according to  any of the preceding claims , wherein Z is 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound for use, according to  any of the preceding claims , wherein R 3  and R 3 ′ are the same and are: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound for use, according to  claim 1 , wherein the compound is selected from:
 4-(picolinimidamido)-N-(4-(picolinimidamido)phenyl)benzamide (3a)   5-(picolinimidamido)-N-(5-(picolinimidamido)pyridin-2-yl)picolinamide (3b)   3-chloro-N-(2-chloro-4-(picolinimidamido)phenyl)-4-(picolinimidamido)benzamide (3c)   3-chloro-N-(3-chloro-4-(picolinimidamido)phenyl)-4-(picolinimidamido)benzamide (3d)   2-chloro-N-(2-chloro-4-(picolinimidamido)phenyl)-4-(picolinimidamido)benzamide (3e)   2-chloro-N-(3-chloro-4-(picolinimidamido)phenyl)-4-(picolinimidamido)benzamide (3f)   2-isopropoxy-N-(2-isopropoxy-4-(picolinimidamido)phenyl)-4-(picolinimidamido)benzamide (3g)   4-(picolinimidamido)-N-(5-(picolinimidamido)pyridin-2-yl)benzamide (3h)   3-fluoro-N-(2-fluoro-4-(picolinimidamido)phenyl)-4-(picolinimidamido)benzamide di-trifluoroacetate (3i)   3-fluoro-N-(3-fluoro-4-(picolinimidamido)phenyl)-4-(picolinimidamido)benzamide di-trifluoroacetate (3j)   2-fluoro-N-(2-fluoro-4-(picolinimidamido)phenyl)-4-(picolinimidamido)benzamide di-trifluoroacetate (3k)   2-fluoro-N-(3-fluoro-4-(picolinimidamido)phenyl)-4-(picolinimidamido)benzamide di-trifluoroacetate (3l)   N,N′-(ethane-1,2-diylbis(4,1-phenylene))dipicolinimidamide (17)   N,N′-((carbonylbis(azanediyl))bis(4,1-phenylene))dipicolinimidamide (18)   4-((1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)amino)-N-(4-((1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)amino)phenyl)benzamide (1a)   5-((1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)amino)-N-(5-((1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)amino)pyridin-2-il)picolinamide (1b)   3-chloro-N-(2-chloro-4-((1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)amino)phenyl)-4-((1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)amino)benzamide (1c)   3-chloro-N-(3-chloro-4-((1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)amino)phenyl)-4-((1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)amino)benzamide (1d)   2-chloro-N-(2-chloro-4-((1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)amino)phenyl)-4-((1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)amino)benzamide (1e)   2-chloro-N-(3-chloro-4-((1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)amino)phenyl)-4-((1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)amino)benzamide (1f)   4,4′-(ethane-1,2-diyl)bis(N-(1H-benzo[d]imidazol-2(3H)-ylidene)aniline (13)   1,3-bis(4-((1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)amino)phenyl)urea (14).   
     
     
         13 . A compound of general formula (I) described in any of  claims 1 to 12 , for use in the prevention and/or treatment of diseases caused by protozoan parasites. 
     
     
         14 . The compound for use, according to  claim 13 , wherein the protozoan parasites are of the genera  Leishmania  or  Trypanosoma.    
     
     
         15 . The compound for use, according to  claim 14 , wherein protozoan parasites of the genera  Leishmania  or  Trypanosoma  are of the species  L. aethiopica, L. amazonensis, L. arabica, L. archibaldi, L. aristedesi, L. braziliensis, L. chagasi  (syn.  L. infantum ),  L. colombiensis, L. deanei, L. donovani, L. enriettii, L. equatorensis, L. forattinii, L. garnhami, L. gerbili, L. guyanensis, L. herreri, L. hertigi, L. infantum, L. killicki, L. lainsoni, L. major, L. mexicana, L. naiffi, L. panamensis, L. peruviana, L. pifanoi, L. shawi, L. tarentolae, L. tropica, L. turanica, L. venezuelensis, T. brucei, T. cruzi, T. congolense, T. equinum, T. equiperdum, T. evansi  or  T. vivax.    
     
     
         16 . The compound for use, according to  claim 15 , wherein the protozoan parasites are of the species  T. brucei, T. cruzi  and/or  L. donovani.    
     
     
         17 . The compound for use, according to  any of the preceding claims 13 to 16 , wherein the disease is selected from leishmaniasis, human African trypanosomiasis, animal trypanosomiasis or American trypanosomiasis. 
     
     
         18 . A compound of general formula (I) 
       
         
           
           
               
               
           
         
         or any of the pharmaceutically acceptable isomers, solvates or salts thereof, wherein: 
         R 1 , R 2 , R 3 , R 3 ′, Z, X and Y are described according to any of  claims 1 to 10 , and with the condition that the compound is not: 
       
       
         
           
           
               
               
           
         
         nor a tautomer thereof. 
       
     
     
         19 . The compound according to  claim 18 , wherein the compound is selected from:
 4-(picolinimidamido)-N-(4-(picolinimidamido)phenyl)benzamide (3a)   5-(picolinimidamido)-N-(5-(picolinimidamido)pyridin-2-yl)picolinamide (3b)   3-chloro-N-(2-chloro-4-(picolinimidamido)phenyl)-4-(picolinimidamido)benzamide (3c)   3-chloro-N-(3-chloro-4-(picolinimidamido)phenyl)-4-(picolinimidamido)benzamide (3d)   2-chloro-N-(2-chloro-4-(picolinimidamido)phenyl)-4-(picolinimidamido)benzamide (3e)   2-chloro-N-(3-chloro-4-(picolinimidamido)phenyl)-4-(picolinimidamido)benzamide (3f)   2-isopropoxy-N-(2-isopropoxy-4-(picolinimidamido)phenyl)-4-(picolinimidamido)benzamide (3g)   4-(picolinimidamido)-N-(5-(picolinimidamido)pyridin-2-yl)benzamide (3h)   3-fluoro-N-(2-fluoro-4-(picolinimidamido)phenyl)-4-(picolinimidamido)benzamide di-trifluoroacetate (3i)   3-fluoro-N-(3-fluoro-4-(picolinimidamido)phenyl)-4-(picolinimidamido)benzamide di-trifluoroacetate (3j)   2-fluoro-N-(2-fluoro-4-(picolinimidamido)phenyl)-4-(picolinimidamido)benzamide di-trifluoroacetate (3k)   2-fluoro-N-(3-fluoro-4-(picolinimidamido)phenyl)-4-(picolinimidamido)benzamide di-trifluoroacetate (3l)   N,N′-(ethane-1,2-diylbis(4,1-phenylene))dipicolinimidamide (17)   N,N′-((carbonylbis(azanediyl))bis(4,1-phenylene))dipicolinimidamide (18)   4-((1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)amino)-N-(4-((1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)amino)phenyl)benzamide (1a)   5-((1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)amino)-N-(5-((1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)amino)pyridin-2-il)picolinamide (1b)   3-chloro-N-(2-chloro-4-((1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)amino)phenyl)-4-((1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)amino)benzamide (1c)   3-chloro-N-(3-chloro-4-((1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)amino)phenyl)-4-((1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)amino)benzamide (1d)   2-chloro-N-(2-chloro-4-((1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)amino)phenyl)-4-((1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)amino)benzamide (1e)   2-chloro-N-(3-chloro-4-((1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)amino)phenyl)-4-((1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)amino)benzamide (1f)   1,3-bis(4-((1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)amino)phenyl)urea (14).   
     
     
         20 . A pharmaceutical composition comprising a compound of general formula (I) described according to any of  claims 18 to 19 , together with a pharmaceutically acceptable excipient, adjuvant and/or carrier. 
     
     
         21 . The pharmaceutical composition, according to  claim 20 , which further comprises another antiparasitic agent.